Welcome to SIOP 2022 Interactive Programme
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- Rajkumar Venkatramani (United States of America)
- Gianni Bisogno (Italy)
PRIMARY LUNG CARCINOMA IN CHILDREN AND ADOLESCENTS: AN ANALYSIS OF THE EUROPEAN COOPERATIVE STUDY GROUP FOR PEDIATRIC RARE TUMORS (EXPERT)
- Michael Abele (Germany)
Abstract
Background and Aims
Primary lung carcinomas are very rare childhood tumors with an incidence of <2/1,000,000 per year as defined by the European Cooperative Study Group for Pediatric Rare Tumors (EXPeRT). They represent a challenge to treating physicians as there are few reports on these diseases at this age and no specific recommendations are available. This collaborative analysis of the EXPeRT group was conducted to improve knowledge about the treatment and prognosis of primary lung carcinomas in pediatric patients.
Methods
A retrospective European analysis of all pediatric patients (0-18 years) with primary lung carcinomas prospectively collected in the EXPeRT databases between 2000 and 2021 was performed. Clinical data including outcomes were analyzed.
Results
Thirty-eight patients were identified with a median age of 12.8 years at diagnosis (range 0 to 17 years). Mucoepidermoid carcinoma (MEC) was the most common entity (n=20), followed by adenocarcinoma (n=12), squamous cell carcinoma (SCC; n=4), adenosquamous carcinoma (n=1) and small-cell lung cancer (n=1). Lymph node metastases occurred rarely in patients with MEC (2 cases), and 19 patients achieved durable remission after surgical resection only. One patient with MEC died after progression of metastasis. Patients with histology other than MEC often presented with advanced disease (stage IV in 14 of 18 cases) and needed multimodality treatment. They had a combined survival rate of 44%. While all patients with SCC died, the 12 patients with adenocarcinoma had a survival rate of 50%.
Conclusions
Primary lung carcinoma occur rarely in children. While patients with MEC have a favorable outcome with a survival rate of 95%, patients with other lung carcinoma entities have an unfavorable outcome despite multimodality treatment strategies. This analysis will help propose consensus guidelines for diagnosis and therapy.
BONE MORPHOGENETIC PROTEIN RECEPTOR 2 (BMPR2) AS A POTENTIAL GERMLINE DRIVER IN JUVENILE POLYPOSIS SYNDROME (JPS)
- Suzanne P. Macfarland (United States of America)
Abstract
Background and Aims
Juvenile Polyposis Syndrome (JPS) is a cancer predisposition syndrome characterized in some cases by germline mutations in BMPR1A or SMAD4. However, in 40-60% of patients the germline driver is unknown. Next-generation sequencing of a cohort of JPS patients identified bone morphogenetic protein receptor 2 (BMPR2) as a candidate driver in one mutation-negative JPS patient with high polyp burden.
Methods
Under an IRB-approved protocol, patient-derived, three-dimensional colonoids were established from adjacent colon and polyp tissue of this individual, as well as an individual with a BMPR1A deletion. Proliferation and metabolic activity of each organoid line were measured by Ki67 staining, EdU labelling, and cell titer glo (CTG) assay alongside age- and sex-matched controls. Relative RNA and protein expression levels of known drivers and downstream effectors were examined by RT-qPCR and Western blot, respectively.
Results
Distinct phenotypic differences are evident between colonoids from an individual with a BMPR1A deletion and BMPR2 variant colonoids, such as increased crypt budding and Ki67 staining. CTG assay data indicate higher metabolic activity in BMPR2 variant colonoids in comparison to normal controls (p= 0.0104). Through Western blot analysis, BMPR2 variant polyp colonoids, specifically, show decreased SMAD4 expression and phosphorylation as well as decreased BMPR1A expression. Downregulation of BMPR1A and SMAD4 expression is also seen by RT-qPCR.
Conclusions
These data demonstrate that clear phenotypic differences exist between colonoid lines established from normal controls, individuals with known JPS predisposition genes, and a novel candidate driver of disease, BMPR2. Proliferation and protein expression data suggest that both known and candidate genotypes are consistent with a hyperproliferative phenotype. In vitro data support BMPR2 as a candidate germline driver of the JPS phenotype, and additional study is ongoing regarding downstream pathway regulation in colonoids with a BMPR2 variant.
NUT CARCINOMA IN CHILDREN AND ADOLESCENTS: THE EXPERT EUROPEAN STANDARD CLINICAL PRACTICE HARMONIZED RECOMMENDATIONS
- Lauriane Lemelle (France)
Abstract
Background and Aims
NUT carcinoma (NC) is a rare and highly aggressive tumor mainly occurring in adolescents and young adults (AYA), defined by the presence of a somatic NUTM1 rearrangement. Aim is to establish internationally harmonized consensus recommendations for the diagnosis and treatment of AYA with NC in the framework of the European Reference Network for Paediatric Oncology (ERN PaedCan).
Methods
The European Cooperative Study Group for Pediatric Rare Tumors (EXPeRT) developed recommendations according to the Consensus Conference Standard Operating procedure methodology and reviewed by external “experts”. No evidence of level I to II exists. Recommendations were developed based on published prospective (Level-III), but more frequently retrospective series (Level-IV), case reports (Level-V) and personal expertise (Level-V). In addition, “strength” of recommendations were categorized by grading (Grade A to E).
Results
Histology is mandatory for the diagnosis of NC, including immunolabelling with anti-NUT antibodies and molecular biology (NUTM1 rearrangement) [Level-V; Grade-A]. Treatment of NC usually combines aggressive approaches in multimodal regimens. Chemotherapy should be considered as first-line treatment (neo-adjuvant VAI-PAI or VDCy-IE) for unresectable or metastatic tumor (i.e. 3 courses), rapidly followed by local treatment [Level-IV; Grade-B]. Referral to a specialized surgical oncology center is highly recommended [Level-V; Grade-A]. In localized NC, a complete microscopic surgical resection should be attempted whenever and as soon as possible, followed by primary irradiation (60-70Gy) and involved lymph nodes area [Level-IV; Grade-B]. For head and neck tumors, a systematic neck dissection might be considered, even if N0 [Level-V; Grade-C]. Adjuvant post-irradiation chemotherapy is recommended, for a total of 9 to 12 courses [Level-IV; Grade-B]. For first-line resected tumors, concomitant adjuvant chemotherapy to RT may be discussed [Level-IV; Grade-B]. Targeted therapies and immunotherapeutic regimens should be delivered in the setting of prospective trials [Level-V; Grade-B].
Conclusions
This project leads to a consensus strategy based on international experience with this very rare disease.